Protective Effects Of Iloprost Research Articles

The protective effect of iloprost on liver tissue as a remote organ in an experimental model of ovarian ischemia/reperfusion

Amaç: Bu deneysel çalışmada iloprostun karaciğer dokusu üzerindeki koruyucu etkisini bir iskemi/reperfüzyon (İ/R) sıçan modelinde araştırmak amaçlanmıştır.Yöntem: Toplam 32 adet dişi Sprague–Dawley sıçan, 4 eşit gruba ayrıldı. Grup 1’deki sıçanlarda overyan dokulara herhangi bir cerrahi işlem uygulanmadı. Sırasıyla Grup 2, 3 ve 4’teki overyan dokulara ise 3 saatlik torsiyon, 3 saatlik torsiyon + 3 saatlik detorsiyon, ve 3 saatlik torsiyon + 3 saatlik detorsiyon + 60 dakikalık iloprost infüzyonu uygulandı. Dokulardan 7 μm kalınlıkta kesitler alındı, hematoksilen–eozin, Masson trikrom ve toluidin mavisi ile boyandı. Kesitler üzerinde ışık mikroskobik inceleme yapıldı.Bulgular: Grup 2, 3 ve 4’te Grup 1’e kıyasla sinüzoidal dilatasyon ve vasküler konjesyonda istatistiksel olarak anlamlı artış tespit edildi (p<0,05). Grup 4’te diğer gruplara kıyasla daha fazla sinüzoidal dilatasyon ve vasküler konjesyon görüldü. Yine Grup 2, 3 ve 4’te Grup 1’e kıyasla daha fazla enflamasyon, fibrozis, hemoraji ve daha yüksek mast hücre yoğunluğu tespit edildi. Ancak fark istatistiksel olarak anlamlı değildi (p>0,05). Histopatolojik skorlamada Grup 2 ve 4’te benzer, Grup 3’te ise daha yüksek skorlar gözlendi.Sonuç: İloprostun İ/R hasarına karşı karaciğer dokusu üzerinde koruyucu etkileri olduğu sonucuna varılmıştır.

Dissecting the Cellular Mechanism of Prostacyclin Analog Iloprost in Reversing Vascular Dysfunction in Scleroderma.

Intravenous iloprost improves Raynaud's phenomenon (RP) and promotes healing of digital ulcers in systemic sclerosis (SSc; scleroderma). Despite a short half-life, its clinical efficacy lasts weeks. Endothelial adherens junctions, which are formed by VE-cadherin clustering between endothelial cells (ECs), regulate endothelial properties including barrier function, endothelial-to-mesenchymal transition (EndoMT), and angiogenesis. We undertook this study to investigate the hypothesis that junctional disruption contributes to vascular dysfunction in SSc, and that the protective effect of iloprost is mediated by strengthening of those junctions. Dermal ECs from SSc patients and healthy controls were isolated. The effect of iloprost on ECs was examined using immunofluorescence, permeability assays, Matrigel tube formation, and quantitative polymerase chain reaction. Adherens junctions in SSc were disrupted compared to normal ECs, as indicated by reduced levels of VE-cadherin and increased permeability in SSc ECs (P < 0.05). Iloprost increased VE-cadherin clustering at junctions and restored junctional levels of VE-cadherin in SSc ECs (mean ± SD 37.3 ± 4.3 fluorescence units) compared to normal ECs (mean ± SD 29.7 ± 3.4 fluorescence units; P < 0.05), after 2 hours of iloprost incubation. In addition, iloprost reduced permeability of monolayers, increased tubulogenesis, and blocked EndoMT in both normal and SSc ECs (n ≥ 3; P < 0.05). The effects in normal ECs were inhibited by a function-blocking antibody that prevents junctional clustering of VE-cadherin. Our data suggest that the long-lasting effects of iloprost reflect its ability to stabilize adherens junctions, resulting in increased tubulogenesis and barrier function and reduced EndoMT. These findings provide a mechanistic basis for the use of iloprost in treating SSc patients with RP and digital ulcers.

Effects of iloprost on experimental ischemia and reperfusion injury in rat ovary

ABSTRACTWe investigated the protective effect of iloprost against ischemia/reperfusion (I/R) injury in rat ovary. We used 32 female Sprague-Dawley rats randomly allocated to four experimental groups: sham, ischemia, I/R and I/R + iloprost. Ovarian torsion was established in all rats except the sham group. The torsion group was exposed to ischemia for 3 h. The detorsion group was exposed to 3 h ischemia applied + 3 h reperfusion. The detorsion + iloprost group was exposed to ischemia for 3 h + reperfusion for 3 h + intravenous (IV) iloprost infusion for 60 min starting at the beginning of reperfusion. Ovaries were removed and prepared for histopathological evaluation. Reduced glutathione (GSH) and malondialdehyde (MDA) were measured in the blood. The total histopathological injury score and MDA level of the ischemia group were significantly higher than for the sham group. Ovarian injury score and MDA level following I/R increased compared to the ischemia group. Iloprost administration reduced the total injury score and MDA level. The GSH level was higher in the I/R + iloprost group than in the I/R group. We concluded that IV iloprost administration reduces I/R injury in rat ovarian tissue.

Effect of iloprost on erythrocyte deformability in rat’s lower extremity undergoing an ischemia reperfusion injury

Ischemia reperfusion injury (I/R) in lower extremity is a frequent and important clinical phenomenon. The protective effect of iloprost on local and distant organ injury due to I/R has been well documented but its effect on erythrocyte deformability needs further investigation. Our aim was to investigate the effect of iloprost on erythrocyte deformability in the infrarenal aorta of rats undergoing I/R. Our study was conducted with 18 Wistar albino rats. Rats were divided into the 3 groups; the randomized control group (group C; n=6), I/R group without iloprost (group I/R; n=6) and I/R group with iloprost - 10 mcg.kg-1, 30 min infusion (group I/R-I; n=6). Packs of erythrocytes were prepared from heparinized blood samples and deformability measurements were done. The comparisons of the control and I/R-I groups revealed similar results (p=0.951). The values of the IR group were significantly higher than those of the control and IR-I groups (p=0.006, p=0.011, respectively). In our study, we detected the unfavourable effects of I/R on erythrocyte deformability, which may lead to disturbance in blood flow and hence tissue perfusion in the infrarenal rat aorta. We also found that Iloprost had beneficial effects by reversing the undesirable effects of I/R (Fig. 1, Ref. 15).

Early protective effects of iloprost, a stable prostacyclin analog, during spinal cord ischemia in a rabbit model

Spinal cord ischemia may develop into paraplegia in some cases during operation of the thoracoabdominal aorta. This is attributable to the vulnerability of spinal motor neurons to ischemia. In this study, iloprost was used as an agent to decrease the severity of ischemia and reperfusion injury to the spinal cord motor neurons. Twenty-one rabbits were randomized into three groups of seven animals each: group A (iloprost not administered), group B (25 ng/kg per minute iloprost), and group S (sham-operated). The spinal cord ischemia model was created by a 15-min occlusion of the aorta just caudal to the renal artery with a balloon catheter. Administration of iloprost began 10 min before occlusion of the aorta, and continued thereafter for 60 min. The pre- and postocclusion arterial pressure and heart rate recordings, results of blood gas analyses, and hematocrit and glucose levels were recorded. The spinal cords were removed after 8-h monitoring of neurologic function. Viable and nonviable motor neurons in the anterior horn of the spinal cord were counted under light microscopy. Any significant alteration in hemodynamics, blood gases, and other physiologic parameters could not be detected within the groups. Iloprost had a moderately hypotensive effect. Neurologic function in terms of Johnson scoring was significantly better in the iloprost group (P<0.05). The number of viable cells was higher, whereas the number of nonviable cells was lower in iloprost group, when compared with the control group (P<0.05). Higher numbers of viable motor neurons were consistent with the neurological findings. As a result of this study we concluded that iloprost infused during clamping of the aorta mitigates the spinal cord injury due to ischemia and reperfusion, and has a significant protective effect.

Beneficial effect of iloprost on the course of acute taurocholate pancreatitis in rats and its limitation by antecedent acute ethanol intake

The effects of stable prostacyclin analogue iloprost on the trypsinogen activation, labilization of lysosomal membranes, lipolytic enzymes activities, histopathological and ultrastructural changes in the pancreas of rats with severe, taurocholate acute pancreatitis (AP), preceded for 6 h by acute ethanol intake have been investigated. Iloprost (1 microg/kg b.w., i.p.) was applied every 6 hours after inducing of taurocholate AP. The antecedent intragastric 40% ethanol intake (5 g/kg b.w.) increased an index of trypsinogen activation in AP lasting 18 h. Treatment with iloprost prevented this increase in the rats with AP given earlier alcohol, and limited the labilization of lysosomal membranes in nonalcoholized rats with AP. Phospholipase A2 and lipase activities were reduced by iloprost only in the rats not given ethanol. The additional damaging effect of acute ethanol abuse prior to AP could be dependent on augmented activation of trypsinogen. The protective effect of iloprost in AP seems to be dependent on the attenuation of trypsinogen activation, decrease of total potential trypsin and the decrease of lysosomal membranes labilization. Its protective effect could be limited in taurocholate acute pancreatitis preceded by acute ethanol intake as evidenced by the differences in the cathepsin B, phospholipase A2 and lipase activities and by histopathological and ultrastructural examination.

Effects of iloprost on vasospasm after experimental spinal cord injury: An electron and light microscopic study

It has been increasingly reported that traumatic and ischemic insults to the spinal cord may produce tissue damage through both direct and indirect mechanisms. In spite of many theories about post-traumatic spinal cord injury, there is still no satisfactory account of the exact mechanism. Vasospasm may be related to the trauma and release of vasoconstrictor or vasoactive amines. This study aims at studying the possible protective mechanisms of iloprost, a stable analogue of prostacyclin, after spinal cord injury on the rabbit. Forty-two adult male rabbits (New Zealand albino) were inflicted injuries by epidural application of an aneurysm clip to the spinal cord. Twenty-one rabbits received an i.v. infusion of 25 µg kg-1 h-1 iloprost. The remaining twenty-one rabbits received an i.v. infusion of saline as the control group. Intravenous treatment started immediately after the infliction of the spinal cord injury and lasted for 1 h. Iloprost treatment had no side effects on the general physiological parameters in the rabbits. Control and iloprost treatment groups were divided into three sub-groups. The first group of animals was deeply anesthetized and spinal cords were removed 15 min after treatment. Second and third group animals were sacrificed in the 3rd and 24th hours respectively. All spinal cords were removed for light and electron microscopic examination. The width of anteriolar smooth muscle cells and the ultrastructural analysis of sulcal arterioles and venules in the ventral median fissure of spinal cords treated by iloprost revealed less thickening in all groups especially on the 24th hour group (p < 0.01), but less thickening was observed on the 3rd hour group. Iloprost-treated groups had limited edema and moderate protection of myelin and axons. These results suggest that iloprost treatment after spinal cord injury has a highly protective effect, and the possible protective effect of iloprost is resolution of vasospasm due to spinal cord injury. [Neurol Res 2001; 23: 843-850]

The protective effect of Iloprost, a PGL2-analogue, on ultrastructure of ischemic and reperfused myocardial myocytes

Iloprost was used in experiments with dogs to investigate its ultrastructure-preserving effects on the myocardium during ischemia and reperfusion, focussed especially on the mitochondria. Ischemia was performed by ligation of the left anterior descending coronary artery (LAD) for 90 min followed by reperfusion of 180 min. Samples were taken from the ischemic and non-ischemic area before ligation of LAD, immediately after ischemia and reperfusion. Iloprost was applicated into the left femoral vein after the end of LAD ligation. Ultrastructural-morphometric analysis revealed that iloprost was able to diminish damages of the mitochondria after ischemia and reperfusion as well. Mitochondrial oedema and intramitochondrial structure degenerations (destruction of cristae and matrix) were minimized in contrast to results of unprotected animals, which had to undergo the same procedure as indicated by volume, volume densities of mitochondria, and of the intramitochondrial compartments, confirmed by independent secondary morphometric parameters. There were no remarkable differences between the corresponding parameters of mitochondria in the ischemic and non-ischemic area.

Early protective effects of Iloprost after experimental spinal cord injury

Serial magnetic resonance (MR) imaging has not yet been validated in the therapy of experimental intracerebral hematomas in a rat model. It is possible to test the effect of local fibrinolysis and aspiration on the clot volume using serial magnetic resonance imaging and different MR-sequences. Experiments were carried out in 22 male Sprague-Dawley rats. Intracerepra I hematoma was produced by injection of fresh autologous blood into the caudate nucleus using a double injection technique. Thirty minutes later 70 rats were treated by injecting 12 µl of recombinant tissue plasminogen activator. MR-imaging was performed immediately after generation of the hematoma and after clot lysis. The clot volume measured in the magnetic resonance images was compared with that obtained in stained histological serial sections at the end of the experiment. Serial MR scanning demonstrated a significant reduction (p<0.07) of hematoma volume after fibrinolysis followed by aspiration of the blood clot. The best correlation between MR- and histological volumetry was found on RF-spoiled FLASH 2D-images. This study documents the efficacy of MRI in detecting and delineating the size of acute intracerebral hematomas and its time course. Local fibrinolysis and aspiration can be simulated in an experimental rat model. [Neural Res 1998; 20: 349-352]

Circadian Reactivity Rhythm of Rat Gastric Mucosa to Restraint-Cold Stress and Indomethacin: Temporal Variation in the Protective Effect of Iloprost

In this study, the time-dependent ulcerogenic effects of restraint-cold stress and indomethacin on the gastric mucosa and the temporal variation in the protective effect of iloprost, a synthetic stable analog of prostacyclin, were investigated in rats synchronized to 12h light and 12h darkness, lights on at 08:00. The severity of gastric ulceration produced by either stress or indomethacin showed marked circadian variation; it was greatest at 11 HALO (hours after lights on) for restraint-cold stress and at 23 HALO for indomethacin. The severity of the induced ulcerogenesis was least at 7 HALO for both stimuli. The protective effect of iloprost against restraint-cold stress was most prominent at 15 HALO and 19 HALO with an approximately 80% protection score. On the other hand, pretreatment with iloprost reduced the indomethacin-induced mucosal injury only at 23 HALO. The circadian variation in the effect of iloprost and in the rhythmic modalities of these two experimental ulcer models are indicative of differences in their underlying mechanisms. In experimental models of ulceration, the circadian time of application of the ulcerogenic stimulus must be considered as an important experimental factor. Moreover, the protective effectiveness of antiulcer drugs can express time-dependent differences and must also be taken into account in investigative research. (Chronobiology International, 14(6), 575–583, 1997)

The value and limitation of iloprost infusion in decreasing skeletal muscle necrosis

Iloprost has been shown to minimize skeletal muscle necrosis when administered before the onset of ischemia in animal experiments, possibly by preventing neutrophil activation. Since patients with acute limb ischemia are seen after the process has begun, we investigated whether iloprost can be protective when given only during reperfusion. After anesthesia, 18 adult mongrel dogs underwent a standard isolated gracilis muscle preparation. In six control animals (group I) the gracilis muscle was subjected to 6 hours of ischemia followed by 48 hours of reperfusion. Group II animals (n = 6) received intravenous infusion of iloprost at a dose of 0.45 μg/kg/hr beginning 1 hour before the onset of muscle ischemia and throughout the experiment (6 hours of ischemia and 1 hour of reperfusion). In addition to the continuous infusion, they received 0.45 μg/kg intravenous boluses of iloprost 10 minutes before the induction of ischemia and 10 minutes before reperfusion. Group III animals (n = 6) had a similar ischemic interval, but were given a bolus of iloprost of 0.45 μg/kg at end ischemia followed by continuous infusion of 0.45 μg/kg/hr for 48 hours during reperfusion. Muscle biopsies were obtained at baseline and after 1 hour of reperfusion in all groups. Additional biopsies were obtained at 48 hours of reperfusion in groups I and III. Myeloperoxidase activity, a marker of neutrophil activation, was measured in all muscle biopsies. At the end of reperfusion, the gracilis muscle was harvested in all animals and weighed. Muscle necrosis was estimated by serial transection, nitroblue tetrazolium histochemical staining followed by computerized planimetry. Iloprost decreased the percentage of muscle necrosis from 58% ± 7% in control animals to 34% ± 3% in group II animals (p < 0.04). However, there was no difference in the percentage of muscle necrosis when iloprost was given during the reperfusion phase only (55% ± 8% vs 58% ± 7% in group III and group I, respectively). Myeloperoxidase activity at 1 hour of reperfusion was higher than the baseline in group II animals (0.10 ± 0.02 vs 0.02 ± 0.01 units/mg tissue protein, p < 0.05). The muscle weight increased significantly at the end of reperfusion in all three groups. However, the percentage increase was not significantly different between the three groups (34% ± 8% vs 32% ± 7% vs 39% ± 12%). Although we confirmed that iloprost decreases muscle necrosis when started before the onset of ischemia, we were unable to show a protective effect when given only during reperfusion. Since there was a statistically significant increase in myeloperoxidase activity after 1 hour of reperfusion, it appears that the protective effect of iloprost is not related to inhibition of neutrophil activation. Contrary to previous belief, iloprost did not prevent a rise in vascular permeability.

The protective effects of Iloprost and thromboxane synthetase inhibitor, UK 38485, against glycerol — Induced acute renal failure in rats

Tissue protective activities of Iloprost, a stable analogue of PGI 2, and of UK 38485, an inhibitor of thromboxane synthetase, were investigated in rats, in which acute renal failure was elicited by the injection of glycerol. The effects of these compounds on PGE 2- and LTC 4-like activities in the kidney tissue were also studied. Glycerol injection caused acute kidney damage as evidenced by light microscopic examination and abundant hematuria. Glycerol injection also caused an increase in tissue PGE 2- and LTC 4-like activities. Although both metabolites were increased, the ratio of PGE 2 LTC 4 was found to be decreased when compared with the control value. Both Iloprost and UK 38485 partially prevented tissue damage due to glycerol and caused an increase in the ratio of PGE 2 LTC 4 . The preventive effects of the drugs were more pronounced when both drugs were used in combination. The participation of arachidonic acid metabolites in the mechanism of the production of kidney damage due to glycerol and possible preventive effects of the compounds are discussed.

Protective effects of iloprost during ischaemia and reperfusion

Protective effects of iloprost during ischaemia and reperfusion

Protective effect of iloprost and UK 38 485 against gastric mucosal damage induced by various stimuli

This study was undertaken to evaluate the efficacy of iloprost and UK 38485 in the prevention of gastric lesions due to restraint-cold stress, ethanol or indomethacin. Prior injection of iloprost to the rats significantly prevented the increase in ulcer index by restraint- cold stress or indomethacin but nonsignificantly reduced the ulcer index induced by ethanol. UK 38 485 at lower doses caused a highly significant decrease in the ulcer index induced by all noxious stimuli used in this study. UK 38 485 also reduced the increased 3H back diffusion due to restraint-cold stress. Higher doses of the compound, however, failed to decrease the mucosal damage due to restraint-cold stress. Combination of iloprost and UK 38 485 produced a further significant decrease in the ulcer index induced by all noxious stimuli and increased 3H back diffusion induced by restraint-cold stress. In relation to these results the importance of PGI 2/TXA2 ratio in the production of gastric mucosal lesions is discussed.